Regulation of innate inflammation by CD40 signaling and intracellular osteopontin

炎症的适当发展对于保护宿主免受微生物感染至关重要，但 炎症偶尔会过度并在宿主中引起附带损害。这种损害可能是 致命的在这个建议中，我们专注于通过以下方式对过度反应的先天免疫进行非常规调节： 适应性免疫这种调节的分子机制目前是难以捉摸的和未探索的。后 成功完成这项研究，我们希望了解适应性免疫的新机制， 诱导先天耐受性。对机械论的理解不仅会对发展产生重大影响， 针对急性炎症的最佳疗法，以及针对慢性炎症的疫苗和疗法， 炎症，包括自身免疫性疾病。 我们的初步数据表明，巨噬细胞和DC的过度TNF产生受到抑制， T细胞通过CD40-CD40L相互作用。我们进一步确定，骨桥蛋白（OPN），一种主要 已知为促炎分子，出乎意料地在抑制肿瘤坏死因子表达中起调节作用。 巨噬细胞通过IRAK1介导的IL-10产生。起调节作用的骨桥蛋白同种型不是 典型的分泌型骨桥蛋白（sOPN），但一种新的细胞内骨桥蛋白亚型（iOPN）。根据我们初步的 数据，本研究的中心假设是：iOPN介导CD40（由T细胞刺激）之间的串扰 和TLR4（由微生物配体刺激）在巨噬细胞和DC中抑制产生的TNF TLR4刺激。在这个R21提案中，我们计划测试这个假设。

Appropriate development of inflammation is essential to protect hosts against microbial infections, but inflammation can occasionally overshoot and cause collateral damages in hosts. Such damages can be deadly. In this proposal, we focus on an unconventional regulation of over-reacted innate immunity by adaptive immunity. Molecular mechanism of such regulation is currently elusive and unexplored. Upon successful completion of this study, we expect to understand the novel mechanism by which adaptive immunity induces innate tolerance. The mechanistic understanding will have a significant impact on developing not only optimal therapies against acute hyper-inflammation but also vaccines and therapies against chronic inflammation, including autoimmune diseases. Our preliminary data suggested excessive TNF production by macrophages and DCs is suppressed by T cells through CD40-CD40L interaction. We further identified that, osteopontin (OPN), a protein largely known as a pro-inflammatory molecule, unexpectedly plays a regulatory role in suppressing TNF expression in macrophages by IRAK1-mediated IL-10 production. The OPN isotype that plays the regulatory role is not the canonical secreted OPN (sOPN) but a novel intracellular isoform of OPN (iOPN). Based on our preliminary data, the central hypothesis of this study is: iOPN mediates crosstalk between CD40 (stimulated by T cells) and TLR4 (stimulated by a microbial ligand) in macrophages and DCs to suppress TNF production generated by TLR4 stimulation. In this R21 proposal, we plan to test the hypothesis.